Is ENTREP1 p.Val353Leu (c.1057G>C) pathogenic?

ENTREP1 p.Val353Leu (c.1057G>C) is classified Uncertain significance in ENTREP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-29). AlphaMissense: ambiguous (0.5444); Very rare (popmax 0.00267%, afr).

How common is ENTREP1 p.Val353Leu (c.1057G>C) in the general population?

ENTREP1 p.Val353Leu (c.1057G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ENTREP1 p.Val353Leu (c.1057G>C)?

AlphaMissense predicts ambiguous (score 0.5444) — an in-silico prediction, not a clinical call.

ENTREP1 p.Val353Leu

c.1057G>C · rs142919162 · VCV3089184

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5444 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
AlphaMissense	0.5444	ambiguous
REVEL	0.304	indeterminate
SaProt	LLR -10.64	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 58 kb · p 0.22 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V200L vs ClinVar V353L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,920 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000743% 12/1,614,060 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,460
European (non-Finnish)	0.000847%	118,005

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ENTREP1
Protein: p.Val353Leu
Coding: c.1057G>C
MANE Select: NM_001347995
dbSNP: rs142919162
Type: single nucleotide variant
Location: chr9:69383733 (GRCh38)
Structure: AlphaFold pLDDT 60.47
Residue 353: the 'mediates interaction with epn1' region

Full ENTREP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENTREP1 p.Ala374Ser Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala418Asp Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala440Ser Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala440Thr Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala448Ser Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala492Val Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala574Pro Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala588Val Conflicting classifications of pathogenicity ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/entrep1-p-val353leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown